each permutation h2 was computed for all genes, along with the difference in mean h2 for the gene set versus the complementary set. As this difference is nearly normally distributed, an enrichment z-statistic was calculated as the observed difference divided by its permutation standard deviation, and a two-sided P-value computed assuming normality. A similar approach was used for continuous predictors, in which the correlation between h2 and the predictor was computed (with z as the correlation divided by its standard deviation). By permuting only zygosity status, the enrichment-z approach preserves the mean twin pair correlations, as well as gene-gene correlation. To control for the complicating effects of mean expression, some analyses (including all KEGG and GO pathway analyses) were performed in which h2 values were corrected for the effect of mean expression in the original and permuted datasets.
